Ephedrine cardiovascular

Chemical Structures. Figure 1 shows the chemical structures for 14 phenylethylamine compounds. Nine of these compounds are used clinically as anorectics (ii-amphetamine, phentermine, diethylpropion, phenmetrazine, phendimetrazine, clotermine, chlorphentermine, benzphetamine, and fenfluramine). Four of these compounds are not approved for clinical use and are reported to have hallucinogenic properties (MDA, PMA, DOM, and DOET). The final compound ( /-ephedrine) is used clinically for bronchial muscle relaxation, cardiovascular, and mydriatic effects. Figure 2 shows the chemical structure for MDMA, the methyl analog of MDA. MDMA is not approved for clinical use and has been reported to produce both LSD-like and cocaine-like effects. 

Ephedrine is the main alkaloid produced in the roots of Ephedra sinica, preparations of which have found medical application in China for at least 5000 years. It was first purified from its natural source in 1887, and its chemical synthesis was achieved in 1927. It was initially used in cardiovascular medicine, but subsequently found wider application in the treatment of mild hayfever and asthma. It is also used as a nasal decongestant and cough suppressant. 

Contraindications Anesthesia with cyclopropane or halothane, diabetes (ephedrine injection), hypersensitivity to ephedrine or other sympathomimetic amines, hypertension or other cardiovascular disorders, thyrotoxicosis... 

Ephedra (ma huang) is a popular botanical incorporated into a variety of formulations for weight loss, energy or performance enhancement, and symptomatic control of asthma. A pharmacodynamic interaction leading to a fatality has been reported with concurrent use of caffeine and ephedra (62), possibly as a result of additive adrenergic agonist effect of the ephedrine alkaloids and caffeine on the cardiovascular system and the CNS (63). Ephedra was recently withdrawn from the market (64). 

Interest in ephedrine in Western medicine was created by the classical investigations of Chen and Schmidt, which began in 1923 as a result of a Chinese druggist s assurance that ma huang was really a potent drug. These workers reported the cardiovascular effects of the alkaloid, its similarity to epinephrine, and its absorption from the intestinal tract. Numerous clinical and experimental studies soon followed, and the use of ephedrine spread so rapidly that several tons of the alkaloid are now consumed yearly. Synthetic ephedrine (racemic) was first prepared in 1927 and marketed under the name Ephetonin (Goodman and Gilman, 1955). 

The shorter the time interval between doses, the smaller the pressor response to each subsequent dose. Tachyphylaxis probably represents a dynamic blockade of the adrenergic receptors. Ephedrine, for example, activates the receptor, and this activation persists until the drug is completely eliminated. Before the drug is eliminated, however, the arterial pressure returns toward the control level because of compensatory cardiovascular changes, involving only an apparent loss of activity rather than a real one. When another dose is then administered, it acts on receptors still activated so that the pressor response obtained is less than expected. 

In summary, based on the cardiovascular responses that can be observed, it can be stated that ephedrine activates the same adrenergic receptors as does epinephrine but is less potent and has a longer duration of action. 

Cardiovascular toxicity is also frequently encountered in poisoning. Hypotension may be due to depression of cardiac contractility hypovolemia resulting from vomiting, diarrhea, or fluid sequestration peripheral vascular collapse due to blockade of -adrenoceptor-mediated vascular tone or cardiac arrhythmias. Hypothermia or hyperthermia due to exposure as well as the temperature-dysregulating effects of many drugs can also produce hypotension. Lethal arrhythmias such as ventricular tachycardia and fibrillation can occur with overdoses of many cardioactive drugs such as ephedrine, amphetamines, cocaine, tricyclic antidepressants, digitalis, and theophylline. 

Many United States consumers have embraced the use of botanicals and other supplements as a "natural" approach to their health care. Unfortunately, misconceptions regarding safety and efficacy of the agents are common, and the fact that a substance can be called "natural" of course does not guarantee its safety. In fact, these products can be adulterated, misbranded, or contaminated either intentionally or unintentionally in a variety of ways. Furthermore, the doses recommended for active botanical substances may be much higher than those considered clinically safe. For example, the doses recommended for several Ma-huang preparations contain three to five times the medically recommended daily dose of the active ingredient, ephedrine—doses that impose significant risks for patients with cardiovascular disease. 

Non-selective beta-agonists (ephedrine, orciprenaline) are now rarely used because of the higher incidence of cardiovascular side-effects by their action on beta-1 receptors... 

Ephedrine (108), isolated from the Chinese plant Ephedra sinaica, was approved as one of the first bronchodilators and cardiovascular agents. This discovery led to a variety of such antihypertensive agents including P-blockers (4). 

The cardiovascular effects, subjective effects, and abuse potential of single intranasal doses of ephedrine 5 and 10 mg have been compared with oral doses of (—)ephe-drine 50 mg in 16 healthy Caucasian men with no drug/ alcohol/nicotine abuse or dependence (5). Intranasal ephedrine caused an increase in blood pressure but associated orthostatic hypotension. 

The authors concluded that ephedrine was very largely responsible for the cardiovascular toxicity. 

Tricyclic antidepressants inhibit the uptake of catecholamines, such as ephedrine, into sympathetic neurons and can enhance their cardiovascular effects (41). 

The authors suggested that even the small amounts of ephedrine present as additives in some local anesthetics can have a marked effect on the cardiovascular system. 

Samenuk D, Link MS, Homoud MK, Contreras R, Theoharides TC, Wang PJ, Estes NA 3rd. Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin Proc 2002 77(1) 12-16. 

A 68-year-old man developed total spinal anesthesia after the administration of 20 ml of ropivacaine 1% without a prior test dose via an epidural catheter, which was inadvertently placed intrathecally (83). Initial aspiration of both the Touhy needle and the catheter failed to identify the intrathecal position of the catheter. The patient noted weakness in his right leg immediately after the end of the injection. This was followed by weakness in his right arm, asystole, apnea, and loss of consciousness. Ventricular escape beats were noted and sinus rhythm returned after mask ventilation with 100% oxygen and the administration of atropine 1 mg and ephedrine 50 mg. He was able to open his eyes, but remained apneic and was therefore intubated and ventilated. Cardiovascular stabihty was maintained with incremental boluses of ephedrine to a total of 60 mg. He regained consciousness and was successfully extubated 145 minutes later. AH sensory and motor deficits had resolved within 8 hours and no neurological deficit or transient neurological symptoms were detected 5 days later. 

In a placebo-controUed study of induction of anesthesia with a combination of propofol -f fentanyl in 90 patients aged over 60 years, prophylactic intravenous ephedrine 0.1 or 0.2 mg/kg given 1 minute before induction of anesthesia significantly attenuated the fall in blood pressure and heart rate that is usually observed (14). Prophylactic use of ephedrine may be useful in preventing the occasional instances of cardiovascular collapse recorded after induction of anesthesia using these agents in elderly people. 

An anaphylactic reaction occurred in a 77-year-old woman 5 minutes after the start of a vancomycin infusion, when she had received only 40 mg (88). She became unconscious and had a severe cardiovascular collapse, from which she was resuscitated with intravenous ephedrine and adrenaline. 

Many cases of serious adverse effects and even fatalities have been reported that were linked with ephedra or ephedrine administration over the last 10 years. Haller and Benowitz published a review of 140 reports of adverse events related to the use of ephedra alkaloids that were submitted to the FDA between June 1997 and March 1999. Using standardized rating system for assessing causation, 31% of the cases were considered to be definitely or probably related to the use of ephedra alkaloid-containing supplements, and another 31% were deemed to be possibly related. Among these adverse events, 47% involved in cardiovascular symptoms and 18% involved the CNS. Hypertension was the most frequent adverse effect, followed by palpitations, tachycardia, or both stroke and seizures. Ten events led to death and 13 cases produced permanent disability. 

Studies have shown that resultant effects are similar, regardless of whether pure synthetic ephedrine or naturally occurring ephedra is ingested (24,25). There are,however, significant enantioselective differences between the enantomers in both pharmacokinetic and pharmacodynamic effects. All of the ephedra alkaloids have important effects on the cardiovascular and respiratory systems, but not to the same degree. 

Tashkin DP, Meth R, Simmons DH, Lee YE. Double-blind comparison of acute bronchial and cardiovascular effects of oral terbutaline and ephedrine. Chest 1975 68(2) 155—161. 

Dingemanse J, Guentert T, Gieschke R, Stabl M. Modification of the cardiovascular effects of ephedrine by the reversible monoamine oxidase A-inhibitor moclobemide. J Cardiovasc Pharmacol 1996 28(6) 856—861. 

An article in the Canadian Adverse Reaction Newsletter published their reporting of adverse effects caused by products containing C. aurantium from January 1, 1998 to February 28, 2004 (46). The article lists 16 reports of synephrine associated with cardiovascular events including tachycardia, cardiac arrest, ventricular fibrillation, transient collapse, and blackout. In one case, bitter orange was the sole suspected culprit. In seven others the products also contained caffeine, and in eight cases the product contained both caffeine and ephedrine. Health Canada has issued an advisory stating that synephrine may have effects similar to ephedrine and caution should be used if taking it (47). 

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